Esters of unsaturated polyhydroxy estrane



Patented June 25, 1940 reruns or cuss-mum rounrnaoxr ES'IBAN! Karl Miesehe'r,

Schoh, Basel, of Chemical land wing. Application In Switzerland July 30, 1936 No Dra 6 Claims. Previously the only aliphatic esters of the mlwhich and a diacetate of estradiol and.

esters of compounds of the unsaturated polyhydroxy-estrane series, the acid residues of which contain in the case of the mono-esters more than three carbon atoms or in the case of dior tri- 19 esters together more than four or six carbon atoms, respectively, have a particularly protracted effect which exceeds that of the corresponding acetates. By suitable choice of the acid residues the duration of the effect may be varied within certain limits, which is of great importance for therapeutic purposes.

It is known that the 3-monobenzoate of estradiol has a certain protracted eflect. It could however not be anticipated in any way that com- 20 pounds can be produced according to the present process which considerably surpass the 3-monobenzoate as regards the duration of the effect.

If 257 each, for exampleof an estradiol ester, dissolved in- 0.5 cc. of sesame oil, are in- Jected into female castrated rats, for instance on two consecutive days, and the duration of the estrus by vaginal smears is ascertained, it is found that the 3-monobenzoate, the ll-monoacetate, and the diacetate act only for 15-19 days (the 3-monoacetate even 3 days only). However, the duration of the estrus, for example when using the l'l-mono-n-butyrate, is 2'7 days, in the case of the dipropionate 60 days, in the case of the 3-monocaprlnate and the 3-monopalmitate 76 days, in the case of the divalerate 80 days, in the case of the 3-monostearate 81 days, in the case of the l'l-monovalerate 8'7 days, and in the case of the dicaprinate even 150 days.

40 plete esteriflcation of compounds of the unsaturated polyhydroxy-estrane series with suitable aliphatic acylating agents of the mono-carboxylic acid series.

Similarly substituted diand tri-esters are obtained in a manner known in itself. 3-monoesters are produced advantageously according to the method of Schotten-Baumann. When working in the absence of alkalies under careful conditions of reaction, one succeeds in obtaining l'l-mono-esters or 16, l'l-di-esters, particularly when using free acids or anhydrides thereof. By

further esterifying the partially esterified compounds with similarly or differently constituted acylating agents, similarly or mixed substituted dior tri-esters can be produced.

Suitable acylating agents are, for example, the corresponding aliphatic acids themselves anhydrides, halides or esters of low molecular weight (exchange esteriflcation) so or also corresponding ketenes. The said alilnfllllt y in Basi or their formed with alcohols andcaesar July a. 1m, serial- (Cl. zoo-s91) phatic acids may be straight or branched, saturated or unsaturated. Suitable acid components are, for example, propionic acid polyesters), butyric acids, crotonic acid, valeric acids, caproic I acids, oenanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid. myristic acid, palmitic acid, stearic acid and the like, further also suitable esters of carbonic acid. Esters with substituted acids, for example, acids containing hydroxyl or halogen, such as lactic acid, are also of interest. In the case of mixed esters one of the acid components may be, for example, formic acid or acetic acid.

By the expression compounds of the unsaturated polyhydroxy-estrane series there are to be understood, for example, estradiol, dihydroequilenine and estriol.

The new compounds peutic use.

The following examples illustrate the inven-' tion, the parts being by weight:

Example 1 A mixture of 2.2 parts of estradiol, 12' parts of pyridine and 9 parts of propionic anhydride is heated for some time at C. After cooling the mass is gradually diluted while shaking with are applicable for thera- 300 parts ofwater, whereupon the estradiol dipropionate crystallizes directly. After standing time the crystals are filtered ofl and washed with N-sulfuric acid; water, saturated sodium bicarbonate solution and finally with water. For purification the compound is recrystallized from aqueous methanol. It melts at 104-105 C.

The same compound is obtained by propionylating estradiol 3- or l'l-monopropionate of melting point 124.5-125. 5 C. and 199-200 0., respectively.

Example 2 A mixture of 2.4 parts of estradiol, 12 parts of pyridine and 10 parts of n-butyric anhydrlde is heated for some time at C. It is then cooled and mixed while stirring with 250 parts of water, whereupon an oil separates. The latter is extracted with ether and the ethereal solution is washed successively with N-sulfuric acid, water, N-sodium carbonate solution and water. The dried ethereal solution is freed from ether and the residual oil distilled in a high vacuum. The estradiol vdi-n-butyrate thus obtained may be recrystallized from. a mixture of methanol and water. It melts at 64-65 C.

The estradiol di-iso-butyrate of melting point 100.5101.5 C. is also obtained in quite analo ous manner.

. Example-l 2.3 parts of estradiol are mixed with 12 parts of pyridine and 10 parts of n-valeric anhydride and the mixture is heated for some time at 115 C. in

the oil bath. The cooled solution is mixed with 250 parts or water, whereuponan oil separates; this is extracted with ether. The parated ethereal solution is washed successively with N- 5 sulfuric acid. water, N-sodium carbonate solution and water and then dried. The ether is then removed and the residue purified by distillation in a high vacuum. The estradiol di-n-valerate forms a yellowish oil.

The estradiol di-iso-valerate in also obtained in quite analogous manner.

The reaction may also be carried out in the presence of other tertiary bases, such as for example dimethylaniline, quinoline, and the like, or

also without such bases.

E's-ample l 1.5 parts of estradiol are dissolved in 15 parts of pyridine and -mixed while shaking with 4.5

' parts of caprinyl bromide. The mixture is allowed to stand for 12 hours, whereupon it is mixed with g- -suliuric acid Example 5 Example 6 1.5 parts of estradiol are dissolved in 500 parts 01' N-caustic soda solution and mixed while shaking with 6.7 parts of caprinyl chloride added in doses. After 20 minutes the mass is extracted with ether and the ethereal solution is washed with N-caustic soda solution and water. After expelling the ether the estradiol 3-monocaprinate is purified by treatment with aqueous methanol. It is obtained in the form of leaflets melting at The estradiol 3 -monocaproate or -caprylate may also be obtained in analogous manner.

Example 7 A solution 01' 1.5 parts of estradiol in 500 parts oi N-caustic soda solution is mixed while shaking strongly with 4.8 parts of palmityl chloride added in small portions. After $5 hour the mass is acidified while coo then extracted with ether and the separated ethereal solution is washed with N-caustic soda solution and water. The ether is then distilled ofl and the residual estr ol monopalmitate is recrystallized from a mixture of acetone and water. It melts at IO-71 C.

and water and then dried.

lsample 8 Asoiution oil.5partsotestradiolin500parts oi N-caustic soda solution is mixed while vigorously stirring with a solution of 5.2 parts 0! 5 stearyl chloride in 5 parts of benzene added in when the reaction is complete i caustic soda solution The residual estradiol 3-mon0stearate obtained aiter expelling the sol u vent forms crystals of melting point 78-79 C. It

I may be crystallized from acetone.

Example 9 at II 2.7 parts oi estradiol, 12 parts of pyridine and 2 parts of n-butyric anhydride are allowed to stand at room temperature and worked up in the usual manner, the estradiol l'l-mono-n-butyrate of melting point ms-wr c. is obtained amirepeated recrystallization. The same compound is obtained for example by the action oi n-butyric acid on estradiol in the heat,.the operationbeing conducted in a closed vessel, if desired. The l'l-mono-iso-butyrate of melting point 188-1835 C. and the l'l-mono-n-valerate of melting point 144-1445 C. as well as similar compounds are obtained in similar manner.

By further esterii'ication it is possible to obtain similarly and difl'erently acylated di-esters of 40 estradiol, such as for example the estradiol 3,1!- di-n-valerate, the estradiol 3-acetate-l'l-n-valerate and the like.

Example 10 45 1 part of estradiol is mixed with 1.3 parts of capric acid and heated in a nitrogen atmosphere for sometime to about 200 C. The mixture is extracted with ether, the ethereal solution is washed with soda solution and water, dried and 50 the solventexpelled. The estradiol l'l-monocaprinate of melting point 112-1125 0. is obtained from the residue by repeated recrystallisation from aqueous methanol.

The esterification with the aid of the free acid 58 described above may also be carried out advantagously in the presence of a condensing agent.

Instead oi the above mentioned acid their elters with low alcohols, for example capric acid methyl ester, may also be used for the acylation. l0

Dihydro-equilenlne and estriol may be converted in analogous manner into their corresponding esters, such as for example the diproprionates, the dibutyrates, the propionate-butyrates, the triproprionate, the tributyrates, the tricaprinate. 05 and the like.

What we claim is:

l. The aliphatic acylated compounds of the unsaturated polyhydroxy-estrane series, the acid residues oi which contain .in the case of the 7 mono-esters more than three carbon atoms, in the case of the di-esters together more than four carbon atoms and in the case of the tri-esters together more than six carbon atoms.

2. The aliphatic acylated mono-esters oi Is estradiol, the acid residues of which contain more than three carbon atoms.

3. The aliphatic acylated di-esters of estradiol, the acid residues of which contain more than four carbon atoms.

4. The estradiol dipropionate or melting point 104-105 C. of the formula CHI H CH1.CH:.C0.0

5. The di-alkyl carbonic acid esters of estradiol, the acid residues of which contain more than four carbon atoms. 1

6. The estradiol-di-ethylcarbonate of meltin point 138-139 C. or the formula 5 cm H KARL MIESCHER- CAESAR SCHOLZ. 

